The initial discovery that Gram-negative bacteria, such as Vibrio fischeri and Pseudomonas aeruginosa, employ small diffusible molecules, namely N-acyl homoserine lactones, to globally regulate the production of secondary metabolites and proteins, initiated a new area in microbiological research, the field of quorum sensing. Subsequently, other quorum sensing systems and signaling molecules have been identified, including oligopeptides in Gram-positive bacteria, such as Staphylococcus aureus. Quorum sensing systems seem to be evolutionary conserved and many of them are involved in the control of bacterial pathogenesis. With the emergence of more highly antibiotic-resistant bacterial strains (superbugs), most notably methicillin-resistant S. aureus (MRSA) and P. aeruginosa, new approaches for combating bacterial infections are desperately needed. In fact, the Center for Disease Control and Prevention (CDC) has estimated that 94,000 invasive MRSA infections occurred in the U.S in 2005 and more than 19,000 Americans died from these infections - more than annual HIV/AIDS casualties. Bacterial quorum sensing signaling molecules might represent such new targets for anti-infective immunotherapy. The powerful combination of chemistry and molecular biology will be harnessed to provide a solid rational basis for quorum quenching therapeutic agents. The specific aims of our R01 application are: (1) Therapeutic targeting of AHL-based Quorum Sensing in Pseudomonas aeruginosa; and (2) The agr Quorum Sensing System in Staphylococcus aureus as target for Immunotherapy.